PO.PS01.01 · 人群科学
一种用于癌症基因组学中突变特征识别和病因归属的泛系统方法
A pan-system approach for mutational signature identification and etiology assignment in cancer genomics
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：体细胞突变在正常细胞和癌细胞的基因组中累积。诱变剂在体细胞突变上留下特征性的基因组模式，称为突变特征。准确识别突变特征对于将遗传毒性暴露和内源性过程与癌症病因相联系至关重要。然而，技术假象、测序噪声和平台异质性常常损害特征检测的保真度，限制了机制见解和生物标志物发现。
方法：我们开发了 SigRescueR，一种泛系统计算工具，可在多种测序平台上进行噪声校正和稳健的突变特征识别。该框架整合了自适应假象过滤、稳健的特征重建，以及基于余弦相似度的信号拯救，涵盖多种突变类别，包括单碱基替换（SBS）、插入和缺失（indel）、双碱基替换（DBS）和链偏倚突变类别。
结果：我们将 SigRescueR 应用于迄今为止汇集的最大规模实验衍生突变谱集合，涵盖 42 个模型系统中超过 4,200 个全基因组测序谱，这些系统在标准化实验条件下暴露于 120 多种诱变剂。跨人类、小鼠、大鼠、鸡和秀丽隐杆线虫（C. elegans）模型的比较分析揭示了 49 个稳健的实验性突变特征。若干实验衍生特征反映了暴露于相同试剂或相关化学品的物种和模型之间保守的 DNA 损伤模式，而另一些则是物种或模型特异性的，提示突变反应中存在系统依赖性变异。此外，若干实验性突变特征对应于已确立的 COSMIC 模式，而另一些则代表人类癌症中先前未表征的 DNA 损伤过程。重要的是，该汇编使得先前无法解释的 COSMIC 特征（即 SBS94 和 SBS95）能够进行病因归属，归因于特定的环境暴露。
结论：总之，SigRescueR 和该汇编提供了对诱变过程统一的高分辨率视角，将分子毒理学、癌症基因组学和生物标志物发现联系起来。这一整合框架完善了我们追踪、解释并采取措施预防癌变基因组印记的方式。
查看英文原文 English abstract
Purpose : Somatic mutations accumulate in the genomes of both normal and cancer cells. Mutagens imprint characteristic genomic patterns of somatic mutations, termed, mutational signatures. Accurate identification of mutational signatures is essential for linking genotoxic exposures and endogenous processes to cancer etiology. However, technical artefacts, sequencing noise, and platform heterogeneity often compromise the fidelity of signature detection, limiting mechanistic insights and biomarker discovery.
Methods : We developed SigRescueR , a pan-system computational tool that performs noise correction and robust mutational signature identification across diverse sequencing platforms. The framework integrates adaptive artefact filtering, robust signature reconstruction, and cosine similarity-based signal rescue across diverse mutational classes, including single base substitutions (SBS), insertions and deletions (indels), doublet base substitutions (DBS), and strand-bias mutation categories.
Results : We applied SigRescueR to the largest collection of experimentally derived mutational profiles assembled to date, encompassing over 4,200 genome-wide sequencing profiles across 42 model systems exposed to 120+ mutagenic agents under standardized experimental conditions. Comparative analysis across human, mouse, rat, chicken, and C. elegans models revealed 49 robust experimental mutational signatures. Several experimentally derived signatures reflected conserved DNA damage patterns across species and models exposed to the same agent or related chemicals, while others were species- or model-specific, suggesting system-dependent variability in mutational response. Moreover, several experimental mutational signatures corresponded to established COSMIC patterns, while others represented previously uncharacterized DNA damage processes in human cancers. Importantly, this compendium enabled causal assignment of previously unexplained COSMIC signatures, namely SBS94 and SBS95, to defined environmental exposures.
Conclusion: Together, SigRescueR and this compendium provide a unified, high-resolution view of mutagenesis, connecting molecular toxicology, cancer genomics, and biomarker discovery. This integrative framework refines how we trace, interpret, and incite measures to prevent the genomic imprints of carcinogenesis.
利益披露 Disclosure
M. Zhivagui, None..
S. Al-azzam, None..
J. Au, None..
P. Nguyen, None..
Z. Jiang, None..
M. D. Barnes, None..
L. B. Alexandrov, None.